Carbapenem-resistant Klebsiella pneumoniae infections after liver transplantation: Drug resistance, risk factors and impact on prognosis

Abstract

BACKGROUND

Liver transplant (LT) recipients are susceptible to carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. Comprehensive research addressing the incidence, timing, infection sites, resistance patterns, treatment options, and associated risk factors among LT recipients with CRKP is now lacking.

AIM

To assess the incidence, resistance, therapy, and risk factors of CRKP infections post-LT, and to evaluate the impact of them on prognosis.

METHODS

A retrospective study was conducted, including 430 consecutive patients who underwent LT between January 2015 and June 2023. This study aimed to investigate the risk factors for CRKP infections and their influence on outcomes using logistic regression analysis.

RESULTS

Among the 430 patients who underwent LT, 20 (4.7%) experienced at least one documented CRKP infection within 3 months post-transplantation. The median time from LT to the onset of CRKP infections was 6.5 days. The lungs and bloodstream were the most common sites of CRKP infections. CRKP isolates were relatively susceptible to ceftazidime/avibactam (93.7%), polymyxin B (90.6%), and tigecycline (75.0%) treatment. However, all isolates were resistant to piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, meropenem, and levofloxacin treatment. Recipients with CRKP infections had a mortality rate of 35%, the rate was 12.5% for those receiving ceftazidime/avibactam therapy. Multivariate analysis identified female sex [odds ratio (OR) = 3.306; 95% confidence interval (CI): 1.239-8.822; P = 0.017], intraoperative bleeding ≥ 3000 mL (OR = 3.269; 95%CI: 1.018-10.490; P = 0.047), alanine aminotransferase on day 1 post-LT ≥ 1500 U/L (OR = 4.370; 95%CI: 1.686-11.326; P = 0.002), and post-LT mechanical ventilation (OR = 2.772; 95%CI: 1.077-7.135; P = 0.035) as significant variables associated with CRKP. CRKP infections were related to an intensive care unit length (ICU) of stay ≥ 7 days and 6-month all-cause mortality post-LT.

CONCLUSION

CRKP infections were frequent complications following LT, with poor associated outcomes. Risk factors for post-LT CRKP infections included female sex, significant intraoperative bleeding, elevated alanine aminotransferase levels, and the need for mechanical ventilation. CRKP infections negatively impacted survival and led to prolonged ICU stays.

Key Words: Liver transplantation; Carbapenem-resistant Klebsiella pneumonia; Antibiotic resistance; Infection; Immunosuppression; Risk factors

Core Tip: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections were frequently seen in liver transplant recipients. CRKP isolates were relatively susceptible to ceftazidime/avibactam and polymyxin B. Risk factors for CRKP infections included female sex, significant intraoperative bleeding, elevated alanine aminotransferase levels, and the need for mechanical ventilation. CRKP infections negatively impacted survival and led to prolonged intensive care unit stay.

INTRODUCTION

Liver transplant (LT) recipients are susceptible to infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP)[1-4]. The reported incidence of CRKP infections following LT varies widely, ranging from 2.5%-35%[1,5-9]. Limited antimicrobial options contribute to poor outcomes associated with CRKP infections, with mortality rates reported between 10%-83% among LT recipients[1,2,4-8,10,11].

While some studies have investigated the risk factors for CRKP infections and their impact on LT recipient prognosis[7,12], comprehensive research addressing the incidence, timing, infection sites, resistance patterns, treatment options, and associated risk factors is still lacking. Furthermore, there is a scant exploration of year-to-year trends in CRKP as a proportion of all Klebsiella pneumoniae (K. pneumoniae) isolates in LT recipients. Integrating these aspects could facilitate the development of effective preventive and therapeutic strategies to enhance outcomes for LT recipients affected by CRKP infections. This study seeks to fill this gap in the current literature.

MATERIALS AND METHODS

Study design and patient sample

A total of 439 LT recipients underwent procedures at the Third Xiangya Hospital of Central South University during the study period between January 1, 2015 and June 30, 2023. Finally, 430 cases were included in this study. A total of nine cases were excluded: Four due to donor-derived K. pneumoniae infections, two being minors (< 18 years old), and three due to fatalities within 48 hours from non-functional primary graft or intraoperative hemorrhage. All grafts, except one, originated from brain-dead donors, and a modified piggyback LT technique was uniformly applied. Induction therapy comprised corticosteroids, with over 50% recipients also receiving basiliximab. Maintenance immunosuppression included tacrolimus/cyclosporine, mycophenolate mofetil/enteric-coated mycophenolate sodium, and prednisone, occasionally supplemented with anti-thymocyte globulin in steroid-incompatible cases. Standard perioperative antibiotic prophylaxis consisted of third-generation cephalosporins or carbapenems for 3-5 days. No organs were procured from executed prisoners.

Clinical data collection

Clinical data spanning a period of 8 years were extracted from electronic medical records, encompassing demographics, infection specifics, and other clinical parameters. Follow-up included microbiological data for 3 months and survival outcomes for 6 months post-LT.

Definitions

Infections were defined as per the Centers for Disease Control and Prevention/National Healthcare Safety Network criteria, according to which positive cultures and clinical signs or imaging confirming active infection were required[13]. The infection source was validated by culture-positive sites and corresponding clinical manifestations[13]. CRKP was defined as resistance to at least 1 carbapenem, with minimum inhibitory concentrations ≥ 2 μg/mL for ertapenem or ≥ 4 μg/mL for imipenem or meropenem (Clinical and Laboratory Standards Institute, 2017). Donor derived K. pneumoniae infection was defined as K. pneumoniae infection present in the donor that was transmitted to the LT recipients with clear evidence[14]. Reoperations encompassed both re-transplantation and post-LT laparotomy, while acute rejection was confirmed by biopsy[15]. Mortality due to CRKP was defined as death in the setting of persistent infection[7].

Microbiologic studies

Post-LT, routine cultures of blood, urine, sputum, and abdominal drainage fluid were conducted daily for 5-7 days, extending as needed within the initial 3 months. Additional cultures (e.g., bronchoalveolar lavage fluid, bile, and organ preservation solution) were performed based on clinical judgment. Blood cultures utilized the BD9240 automatic system, with microbial identification via the Bruker mass spectrometry. Susceptibility to ceftazidime/avibactam (CZA) and polymyxin B was assessed by disk diffusion or broth microdilution. Other antimicrobial susceptibilities utilized the automated Vitek-2 system (bioMérieux, Marcyl’Etoile, France).

Statistical analysis

Categorical variables were expressed as frequencies and percentages, continuous variables as mean ± SD or median with interquartile range (IQR). χ² or Fisher’s exact tests assessed categorical variables. Logistic regression models, utilizing a forward stepwise approach, identified risk factors for post-LT CRKP infections with odds ratios (ORs) and 95% confidence intervals (CIs). Initial models included covariates with P < 0.1, sequentially eliminating nonsignificant predictors. CRKP infection impact on 6-month all-cause mortality was evaluated via the log-rank test and the Kaplan-Meier curves. P < 0.05 was considered significant. Analyses utilized the statistical product and service solutions v26.0 software (IBM Corp., Armonk, NY, United States).

RESULTS

General characteristics and prognosis of LT recipients

In the cohort of 430 LT recipients, the mean age was 47.2 years, with females comprising 18.1% (78/430) of the group. The median model for end-stage liver disease score at LT was 23.0. Table 1 summarizes the clinical, laboratory, and demographic characteristics of the patients. The leading cause of the primary liver disease was hepatitis virus-related cirrhosis/necrosis/tumor (n = 319), followed by alcoholic liver disease (n = 32) and mixed cirrhosis (n = 24). Infections within 2 months prior to LT accounted for 39.5% (170/430) of the cases, predominantly pulmonary infections (87.6%, 149/170), with a few cases of abdominal/biliary infections (3.5%, 6/170), urinary tract infections (0.6%, 1/170), and multiple-site infections (8.2%, 14/170), all of which initially presented with pulmonary infections.

Table 1 Demographic, laboratory, and clinical variables of 430 liver transplant recipients, mean ± SD/n (%).

Characteristics	Value	Range
Recipient age (years)	47.2 ± 10.6	18-73
Recipient gender (female)	78 (18.1)
Recipient BMI (kg/m2), median (IQR)	22.8 (20.8-25.1)	13.8-37.1
Hospital stay prior to LT (days), median (IQR)	9.0 (1.0-22.0)	1-161
MELD score at LT, median (IQR)	23.0 (15.0-30.0)	6-40
Infection within 2 months prior to LT	170 (39.5)
Pre-LT use of broad-spectrum antibiotics	168 (39.1)
Underlying liver diseases	430 (100)
Viral cirrhosis/necrosis/tumor	319 (74.2)
Alcoholic cirrhosis	32 (7.4)
Autoimmune hepatitis	15 (3.5)
Primary biliary cirrhosis	13 (3.0)
Mixed cirrhosis	24 (5.6)
Others1	27 (6.0)
Pre-LT type 2 diabetes	51 (11.9)
Pre-LT creatinine (mg/dL), median (IQR)	0.8 (0.6-1.0)	0.1-10.7
Pre-LT WBC count (× 109/L), median (IQR)	5.2 (3.5-8.0)	0.5-33.6
Pre-LT lymphocyte count (× 109/L), median (IQR)	0.8 (0.5-1.2)	0.1-3.7
Pre-LT platelet count (× 109/L), median (IQR)	70.0 (43.0-106.3)	7.0-491.0
Pre-LT albumin level (g/L), median (IQR)	34.5 (30.7-38.0)	18.0-55.7
Donor age (years)	42.2 ± 13.1	7-68
Steatosis ≥ 30%	43 (10.0)
Cold ischemia time (hour)	6.3 ± 1.4	1.5-9.6
Duration of surgery (minutes), median (IQR)	380.0 (333.0-430.0)	185-710
Intraoperative bleeding (mL), median (IQR)	3000.0 (2000.0-5000.0)	500-27000
Intraoperative RBC transfusion (units), median (IQR)	12.0 (8.0-18.0)	0-44.0
Post-LT infections due to Klebsiella pneumoniae	33 (7.7)
Median interval between the onset of CRKP infections and LT (days), median (IQR)	6.5 (2.0-17.0)	1-116
CRKP infections	20 (4.7)
Post-LT immunosuppressant treatment	430 (100)
Tacrolimus	419 (97.4)
Ciclosporin A	5 (1.2)
Mycophenolate mofetil/enteric-coated mycophenolate sodium	299 (69.5)
Sirolimus	5 (1.2)
Glucocorticoid	430 (100)
Basiliximab	238 (55.3)
Anti-thymocyte globulin	18 (4.2)
ALT on day 1 after LT (U/L), median (IQR)	697.5 (385.0-1276.3)	54.0-8972.0
Creatinine on day 3 after LT (mg/dL), median (IQR)	0.9 (0.7-1.4)	0.3-12.6
Albumin level on day 1 after LT (g/L), median (IQR)	37.1 (33.6-40.6)	22.5-51.9
Post-LT mechanical ventilation	96 (22.3)
Reoperation	17 (4.0)
Acute rejection	68 (15.8)
Post-LT renal replacement therapy	19 (4.4)
ICU stay after LT (days), median (IQR)	6.0 (5.0-7.0)	0-32
Hospitalization stay after LT (days), median (IQR)	26.0 (21.0-30.0)	3-137
All-cause mortality within 6 months after LT	37 (8.6)
CRKP infections-related mortality	7 (1.6)

¹There were 10 cases of cryptogenic cirrhosis, 5 cases of Budd-Chiari syndrome, 3 cases each of hepatolenticular degeneration and transplant liver failure, 2 cases each of drug-induced liver injury, polycystic liver, and familial hereditary amyloidosis.

LT: Liver transplant; BMI: Body mass index; MELD: Model for end-stage liver disease; IQR: Interquartile range; WBC: White blood cell; RBC: Red blood cell; CRKP: Carbapenem-resistant Klebsiella pneumoniae; ALT: Alanine aminotransferase; ICU: Intensive care unit.

Over the 8-year study period, 47 episodes of K. pneumoniae infections occurred among 33 (7.7%) LT recipients. Of these, 32 episodes were identified as CRKP infections, affecting 20 (4.7%) patients within 3 months post-LT. Among the 20 patients with CRKP infections, lung infections were reported in 30.0% (6/20), bacteremia in 15.0% (3/20), intra-abdominal infections in 10.0% (2/20), and multiple-site infections in 45.0% (9/20). The median time from LT to CRKP infections was 6.5 days, with 85% (17/20) occurring within the first month post-LT.

During their hospitalization, 96 patients required mechanical ventilation, 19 underwent renal replacement therapy, and 68 experienced acute rejection post-LT. Additionally, 4.0% (17/430) of cases underwent reoperation. Median lengths of stay in the intensive care unit (ICU) and hospital were 6.0 and 26.0 days, respectively. The 6-month all-cause mortality rate was 8.6% (37/430).

Distribution and drug resistance of pathogens

Among the 20 recipients with post-LT CRKP infections, 45.0% (9/20) experienced infections in ≥ two sites, with pneumonia affecting 50.0% (10/20), bloodstream infections affecting 45.0% (9/20), and abdominal/biliary tract infections affecting 45.0% (9/20) (Table 1).

Regarding the CRKP susceptibility to antibiotics, tigecycline demonstrated sensitivity in 75.0% (24/32) of isolates, polymyxin B in 90.6% (29/32), and CZA in 93.8% (30/32). However, CRKP showed resistance to piperacillin/tazobactam, ceftazidime, cefepime, levofloxacin, cefoperazone/sulbactam, aztreonam, and meropenem (Table 2).

Table 2 Rate of drug-resistance of 32 isolates of carbapenem-resistant Klebsiella pneumoniae to 12 commonly used antibiotics.

Antimicrobial	Number	Percentage
TZP	32	100
CAZ	32	100
CFS	32	100
FEP	32	100
ATM	32	100
MEM	32	100
LVF	32	100
AN	21	65.6
SXT	18	56.3
TIC	8	25.0
POL	3	9.4
CZA	2	6.3

ATM: Aztreonam; TZP: Piperacillin/tazobactam; CFS: Cefoperazone/ sulbactam; CAZ: Ceftazidime; FEP: Cefepime; AN: Amikacin; LVF: Levofloxacin; MEM: Meropenem; TIC: Tigecycline; SXT: Trimethoprim/sulfamethoxazole; POL: Polymixin B; CZA: Ceftazidime/avibactam.

CRKP accounted for 100% (2/2) of all K. pneumoniae isolates in 2015, 100% (1/1) in 2016, 0% (0/1) in 2017, 85.7% (6/7) in 2018, 71.4% (5/7) in 2019, 50% (2/4) in 2020, 46.2% (6/13) in 2021, 80% (8/10) in 2022, and 100% (2/2) in 2023 (Figure 1).

Figure 1 Trend of carbapenem-resistant Klebsiella pneumoniae incidence over 8 years. CRKP: Carbapenem-resistant Klebsiella pneumoniae.

Antibiotic treatment of CRKP infections

In cases of CRKP infections among LT recipients, CZA was administered to eight patients. Among them, CZA was used as monotherapy in three patients and as a part of the combination therapy in five patients. Combination regimens included CZA with colistin sulfate in four patients and with polymyxin B in one patient. Unfortunately, one patient (12.5%) who received CZA and colistin sulfate combination therapy died due to delayed initiation of both the medications. The median time from CRKP infection onset to CZA initiation was 3.5 days (IQR: 1.3-5.0), and the median duration of CZA treatment was 10.0 days (IQR: 6.3-16.0).

Polymyxin B and meropenem combination therapy was administered to four patients, resulting in death for three (75%). Meropenem alone was administered to three patients, resulting in death in one patient (33.3%). One patient received tigecycline and another received trimethoprim/sulfamethoxazole. Additionally, one patient received gentamicin combined with piperacillin-tazobactam, one patient received doxycycline, and one patient received etimicin, all leading to death.

Analysis of the risk factors for CRKP infections after LT

Univariate analysis indicated that female sex (P = 0.009), surgical durations ≥ 450 minutes (P = 0.015), intraoperative bleeding ≥ 3000 mL (P = 0.004), alanine aminotransferase (ALT) levels on day 1 after LT ≥ 1500 U/L (P < 0.001), post-LT mechanical ventilation (P = 0.003), and post-LT renal replacement therapy (P = 0.052) were potential risk factor for CRKP infections (Table 3).

Table 3 Univariate analysis of risk factors for carbapenem-resistant Klebsiella pneumoniae infections within 3 months after liver transplant, n (%).

Variables	With CRKP infections (n = 20)	Without CRKP infections (n = 410)	P value
Female sex	8 (40.0)	70 (17.1)	0.009
Recipient age ≥ 55 years	7 (35.0)	98 (23.9)	0.259
Recipient BMI ≥ 25	5 (25.0)	109 (26.6)	0.875
MELD score at LT ≥ 25	13 (65.0)	181 (44.1)	0.067
Hospital stay prior to LT ≥ 7 days	13 (65.0)	228 (55.6)	0.409
Viral cirrhosis/necrosis/tumor	14 (70.0)	306 (74.6)	0.643
Hepatic tumor	1 (5.0)	72 (17.6)	0.248
Alcoholic cirrhosis	2 (10.0)	30 (7.3)	0.992
Pre-LT diabetes	4 (20.0)	47 (11.5)	0.424
Pre-LT use of broad-spectrum antibiotics ≥ 3 days	11 (55.0)	157 (38.3)	0.135
Pre-LT creatinine ≥ 2 mg/dL	2 (10.0)	29 (7.1)	0.959
Infection within 2 months prior to LT	11 (55.0)	159 (38.8)	0.147
Pre-LT WBC count ≥ 10 × 109/L	2 (10.0)	59 (14.4)	0.825
Pre-LT lymphocyte count ≤ 0.5 × 109/L	3 (15.0)	103 (25.1)	0.447
Pre-LT platelet count ≤ 50 × 109/L	8 (40.0)	135 (32.9)	0.512
Pre-LT albumin level < 30 g/L	4 (20.0)	85 (20.7)	1.000
Donor age ≥ 50 years	8 (40.0)	134 (32.7)	0.497
Steatosis ≥ 30%	2 (10.0)	41 (10.0)	1.000
Cold ischemia time ≥ 360 minutes	11 (55.0)	193 (47.1)	0.488
Duration of surgery ≥ 450 minutes	8 (40.0)	74 (18.0)	0.015
Intraoperative bleeding ≥ 3000 mL	18 (80.0)	236 (57.6)	0.004
Intraoperative RBC transfusion ≥ 12 U/L	13 (65.0)	223 (54.4)	0.352
ALT on day 1 after LT ≥ 1500 U/L	10 (50.0)	74 (18.0)	< 0.001
Creatinine on day 3 after LT ≥ 2 mg/dL	3 (15.0)	60 (14.6)	1.000
Albumin level on day 1 after LT < 30 g/L	2 (10.0)	29 (7.1)	0.959
Post-LT mechanical ventilation	10 (50.0)	87 (21.2)	0.003
Reoperation	2 (10.0)	15 (3.7)	0.184
Acute rejection	3 (15.0)	65 (15.9)	1.000
Post-LT renal replacement therapy	3 (15.0)	16 (3.9)	0.052
Glucocorticoidse ≥ 1500 mg	15 (65.0)	249 (60.7)	0.702
Basiliximab use ≥ 40 mg	8 (40.0)	171 (41.7)	0.880
Anti-thymocyte globulin use	2 (10.0)	16 (3.9)	0.201

LT: Liver transplant; BMI: Body mass index; MELD: Model for end-stage liver disease; WBC: White blood cell; RBC: Red blood cell; CRKP: Carbapenem-resistant Klebsiella pneumoniae; ALT: Alanine aminotransferase.

Finally, the multivariate analysis identified that the variables significantly associated with CRKP were female sex (OR = 3.306; 95%CI: 1.239-8.822; P = 0.017), intraoperative bleeding ≥ 3000 mL (OR = 3.269; 95%CI: 1.018-10.490; P = 0.047), ALT on day 1 after LT ≥ 1500 U/L (OR = 4.370; 95%CI: 1.686-11.326; P = 0.002) and post-LT mechanical ventilation (OR = 2.772; 95%CI: 1.077-7.135; P = 0.035) (Table 4).

Table 4 Multivariate logistic regression analysis of risk factors for carbapenem-resistant Klebsiella pneumoniae infections in liver transplant recipients.

Variables	B	S.E.	Wald	OR (95%CI)	P value
Female sex	1.196	0.501	5.700	3.306 (1.239-8.822)	0.017
Intraoperative bleeding ≥ 3000 mL	1.184	0.595	3.963	3.269 (1.018-10.490)	0.047
ALT on day 1 after LT ≥ 1500 U/L	1.475	0.486	9.215	4.370 (1.686-11.326)	0.002
Post-LT mechanical ventilation	1.020	0.482	4.469	2.772 (1.077-7.135)	0.035

ALT: Alanine aminotransferase; CI: Confidence interval; OR: Odds ratio.

Prognosis of patients with CRKP infections after LT

Within 6 months of LT, seven (1.6%) patients with CRKP infections succumbed to death. A significantly higher proportion of patients with CRKP infections stayed in the ICU for ≥ 7 days post-LT compared to those without CRKP infections (70.0% vs 34.4%; P = 0.001, Pearson’s χ² test). Moreover, patients with CRKP infections had a significantly higher mortality rate within 6 months post-LT compared to those without CRKP infections (35.0% vs 7.3%; P < 0.001). Conversely, no difference was observed in hospitalization stays ≥ 21 days post-LT between recipients with and without CRKP infections (P = 1.000) (Table 5).

Table 5 The postoperative outcome for patients with/without carbapenem-resistant Klebsiella pneumoniae infections following liver transplant, n (%).

Variables	With CRKP infections (n = 20)	Without CRKP infections (n = 410)	χ2	P value
ICU stay after LT ≥ 7 days	14 (70.0)	141 (34.4)	10.490	0.001
Hospitalization stay after LT ≥ 21 days	16 (80.0)	326 (19.5)	0.003	1.000
All-cause mortality within 6 months after LT	7 (35.0)	30 (7.3)	18.583	< 0.001

CRKP: Carbapenem-resistant Klebsiella pneumoniae; LT: Liver transplant; ICU: Intensive care unit.

The Kaplan-Meier curves depicting the 6-month all-cause mortality supported these findings. The survival rate was significantly lower for patients with CRKP infections compared to patients without CRKP infections (log-rank P < 0.001) (Figure 2).

Figure 2 Survival analysis of liver transplant patients. Kaplan–Meier curves showing the impact on 6-month all-cause mortality of carbapenem-resistant Klebsiella pneumoniae infections and without carbapenem-resistant Klebsiella pneumoniae infections. CRKP: Carbapenem-resistant Klebsiella pneumoniae.

DISCUSSION

The LT recipients face heightened susceptibility to drug-resistant infections due to various factors such as malnutrition, extensive surgical procedures, prolonged antibiotic exposure, frequent hospitalizations, and immunosuppressive therapies[5]. Gram-negative pathogens, K. pneumoniae is frequently isolated, with a substantial proportion exhibiting carbapenem resistance, consistent with findings in our study where CRKP constituted 68.1% of K. pneumoniae isolates[4,5]. The incidence of CRKP infections in our cohort was 4.7%, slightly lower than other reports in LT recipients, suggesting variability in regional and institutional prevalence rates[1,5].

Infections primarily involved the lung and bloodstream, with bloodstream involvement observed in 45% of cases, aligning with prior studies highlighting the predilection of CRKP for these sites in LT recipients[1,3,7]. Notably, no urinary tract infections were documented in our cohort, consistent with data from Giannella et al[3], reflecting stringent diagnostic criteria employed in this study compared to broader definitions in previous literature.

Antimicrobial susceptibility testing revealed universal resistance of CRKP isolates to multiple agents including piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, levofloxacin, and meropenem, while showing relatively high susceptibility to CZA, polymyxin B, and tigecycline. It is important to note that while polymyxin E, amikacin, tigecycline, and carbapenems have been recommended as optimal drugs for CRKP-infected solid organ transplant recipients, their use is limited due to factors such as inferior efficacy, resistance, suboptimal pharmacokinetics, or high toxicity rates[16-19]. Notably, CZA demonstrated a favorable response with a mortality rate of 12.5% among recipients receiving CZA therapy, alone or in combination with other agents, underscoring its efficacy compared with conventional therapies associated with higher mortality rates[5,10].

CZA is a preferred agent for most K. pneumoniae carbapenemase- and oxacillinase-48-like-producing organisms with an overall success rate of about 70% and reduced toxicity compared to other regimens commonly used to treat K. pneumoniae carbapenemase-producing infections, which are often polymyxin-based[20-24].

In a study by Chen et al[25], CZA was used in 21 LT recipients with severe CRKP infections after previous treatment failures with other antimicrobials. The study reported promising results, with mortality rates of 28.6%, 38.1%, and 42.9% at 14 days, 30 days, and an all-cause mortality, respectively. However, limited data is available specifically on the efficacy of CZA for CRKP infections in patients after LT. Although the present study observed a low mortality rate of 12.5% in LT recipients receiving CZA monotherapy or combination therapy, it is important to note that due to the small sample size, the present study cannot definitively conclude whether CZA combination therapy was associated with a reduced risk of clinical failure. Further studies with larger sample sizes should be conducted to provide more data on the cure and survival rates after CZA therapy in LT recipients with CRKP infections.

Female sex, intraoperative bleeding ≥ 3000 mL, elevated ALT levels post-LT, and post-LT mechanical ventilation emerged as significant risk factors for CRKP infections in multivariate analysis. These findings are consistent with existing literature and highlight the importance of these factors in predisposing LT recipients to CRKP infections[2,3,5,7].

The finding that female sex was associated with an increased risk of CRKP infections was in line with the study from Abbott et al[26], claiming that the female sex was associated with hospitalizations for septicemia among kidney transplant recipients. One possible explanation for this association could be that female patients are more prone to developing urinary tract infections, which could potentially contribute to the risk of CRKP infections. However, it is noteworthy that in the present study, no LT recipients developed urinary tract infections caused by CRKP, suggesting that the exact reason for the association between the female sex and CRKP infections in this context remains unclear and warrants further investigation.

Regarding massive bleeding during the surgery, the findings of the present study were consistent with those of a previous study assessing 100 consecutive living donor LT patients where massive operative blood loss was an independent risk factor for post-transplantation bacteremia[27].

Elevated ALT was also associated with post-LT CRKP infections in the present study, which has not been previously reported. Although the reasons for this association are uncertain, a plausible explanation may be that a higher level of ALT in the early stage of LT indicates a severer attack caused by the operation due to massive bleeding or severe hypotension during the operation or indicates poor quality of the graft. These conditions could potentially weaken the immune system, or promote the translocation of the intestinal flora, making LT recipients more susceptible to infections. However, these findings should be validated in future large-scale studies to confirm their significance.

Pre-LT use of broad-spectrum antibiotics and infection within 2 months prior to LT, were more frequent among patients with CRKP, although the difference was not significant. Infections mean increased hospitalization and the use of broad-spectrum antibiotics. Hu et al[28] and colleagues also identified that the K. pneumoniae from inpatients was more likely to be imipenem-resistant than isolates from outpatients. In agreement with our findings, a meta-analysis conducted by Liu et al[29] involving 16 studies which involved 3627 participants confirmed that prior hospitalization and previous antibiotic use were associated with CRKP infection.

The impact of CRKP infections on outcomes was profound, with patients experiencing prolonged ICU stays and significantly higher 6-month all-cause mortality compared to those without CRKP infections. This underscores the critical need for effective preventive strategies and optimized treatment protocols to mitigate these adverse outcomes[5,7,9].

Limitations of our study include its retrospective nature, single-center design, and relatively small sample size of LT recipients with CRKP infections. Future studies should aim to validate these findings in larger cohorts and explore additional factors such as colonization with CRKP pre-LT, which may further elucidate the risk profile for post-LT infections[2,3]. Nonetheless, our study provides valuable insights into the epidemiology, risk factors, and management outcomes of CRKP infections in LT recipients, highlighting the urgency for tailored interventions to improve patient outcomes in this vulnerable population.

CONCLUSION

CRKP infections were frequent complications following LT, with poor associated outcomes. Risk factors for post-LT CRKP infections included female sex, significant intraoperative bleeding, elevated ALT levels, and the need for mechanical ventilation. CRKP infections negatively impacted survival and prolonged ICU stay.

ACKNOWLEDGEMENTS

We would like to thank Professor He QN’s contribution to the study design and his helpful advice in writing of the paper.